Deletions within 22q11.2 may be found with high frequency in individuals with DiGeorge syndrome (DGA), Velo-cardio-facial syndrome (VCFS) and other related phenotypes collectively referred to as CATCH22 phenotype. Approximately 80% of CATCH22 patients present with a congenital heart defect of variable severity and complexity. Usually the defect is a conotruncal anomaly or an aortic arch anomaly. Cases with isolated heart defects and deletions within 22q11.2 have also been reported. For these reasons, the CATCH22 locus is thought to harbor one or more genes important for athe normal heart development. We have defined the smallest region of deletion overlap (SRDO) and mapped within it the breakpoint o a balanced translocation breakpoint of a DGA patient. This breakpoint has naturally become the focal point for t he search for a gene(s) responsible for the CATCH22 phenotype. We have identified several transcripts in the breakpoint region but their level of characterization is still insufficient to establish their role in the disease phenotype. With this project we will pursue the identification and characterization of genes at and around athe balanced translocation breakpoint. Our working hypothesis is that there is one or more genes affected by the breakpoint either via physical disruption or position effect. We propose experimental approaches to test both mechanisms. Genes will also be tested for their role in the disease phenotype mainly by mutation analysis in patients who present with a typical phenotype but carry no detectable deletion. The gene(s) responsible for the CATCH22 phenotype may play a role in common, non syndromic, congenital heart defects and will contribute to our understanding of the cardiovascular and craniofacial development.